This proposal describes a 5-year training program for the development of an independent investigator in the area of NO/cGMP signaling and myocardial dysfunction. The principal investigator is a junior member of the faculty in the Department of Anesthesia at the Harvard Medical School with a background in physiology, who now will acquire new knowledge and skills in molecular and cellular biology to advance his academic career. This proposal will focus on the role of NO/cGMP signaling in myocardial dysfunction associated with systemic inflammation. Kenneth D. Bloch, MD, will mentor the principal investigator's scientific development. Dr. Bloch is a recognized expert in the field of NO/cGMP signaling and has extensive experience in training postdoctoral fellows and graduate students. To complement Dr. Bloch's expertise, the training program enlists the expertise of Roger J. Hajjar, MD, as a co-sponsor, who is an expert in myocardial cellular and molecular biology, as well as cardiac gene transfer. In addition, an advisory committee of highly respected physician scientists will provide scientific and career advice. The proposed experiments will examine the role of NOS2, cGMP and cGMP-dependent protein kinase (PKG) in the myocardial dysfunction associated with endotoxemia. Specifically, the applicant proposes to assess whether NOS2 is sufficient or required, but not sufficient, to cause endotoxin-induced myocardial dysfunction. In addition, the contribution of increased myocardial cGMP concentrations and PKG activation to the myocardial dysfunction associated with systemic inflammation will be examined. Studies will be performed on isolated cardiomyocytes, as well as in vivo using transgenic mice and mice subjected to cardiac gene transfer. Together, the proposed studies will illuminate the role of NOS2 and cGMP-dependent signaling in the pathogenesis of myocardial dysfunction associated with systemic inflammation. This award will permit the applicant to take advantage of the outstanding research training environment of the Cardiovascular Research Center of the Massachusetts General Hospital for the acquisition of new knowledge and skills in cell and molecular biology. In addition, a carefully constructed training program has been developed that will permit successful development of an independent research career examining the basic mechanisms of myocardial dysfunction associated with systemic inflammation.